Abstract
The dopamine hypothesis has been proposed as the pathophysiology of schizophrenia（SZ）, and drug discovery has been based on this hypothesis. About 30% of SZ patients do not respond to dopamine D2 receptor blockers and are considered to have treatment‐resistant schizophrenia（TRS）. The DA hypothesis has limitations in explaining the pathogenesis of TRS, and the glutamate（Glu）hypothesis has been proposed as a comprehensive new hypothesis. Recently, magnetic resonance spectroscopy（1H‐MRS）has been used to measure the concentrations of Glu neurometabolites, suggesting abnormalities in the Glu nervous system in SZ. The Glu hypothesis is expected to clarify the pathogenesis of TRS and develop new therapeutic agents.
